Here, we describe a patient with OI caused by a heterozygous mutation in the COL1A2 gene (NM_000089): c.4048G > A, (p.G1350S). Imaging of the spine showed the characteristics of Scheuermann’s disease.
OI, which is commonly known as brittle bone disease, is a relatively rare connective tissue disorder with significant bone manifestations. The prevalence of OI is one in 15–20,000 births . Approximately 90 % of OI cases are caused by mutations in the COL1A1 or COL1A2 gene, leading to a decreased amount of normal type I collagen or production of type I collagen with abnormal structure. Type I collagen is the main protein component of the bone, skin, ligament, tendon, and many other connective tissues. Type I collagen is a heterotrimer containing two α1(I) chains and one α2(I) chain. It is synthesized as a procollagen molecule, and each proα(I) chain contains a typical triple-helical domain of more than 1,000 residues, consisting of a repeating Gly–Xaa–Yaa sequence, which is flanked by two globular extensions, the amino (N-) and carboxyl (C-) terminal propeptides. The two-terminal propeptides are cleaved after the triple helix is formed. Quantitative type I collagen defects often lead to mild OI, whereas structural defects can cause moderate to severe OI. The most common mutation causing structural defects is a single-nucleotide variant resulting in glycine replacement in the essential Gly–Xaa–Yaa triplets . In the present case, mutation of the COL1A2 gene occurred at nucleotide 4048, leading to glycine to serine alteration at p.1350, which is located in the C-terminal propeptide region (p.1120-p.1366). Fewer than 5 % of mutations occur in the C-propeptide domain of procollagen . Once the C-propeptide trimer is folded, the triple-helical region folds in a zipper-like manner toward the N-terminus . A previous study showed that the C-terminal propeptide of proα2(I) is crucial for efficient assembly of type I procollagen heterotrimers . Compared with the proα1(I)-C-propeptide, pathogenic proα2(I)-C-propeptide variants are less common and generally associated with a milder form of OI. Cultured dermal fibroblast cells from patients with pathogenic proα2(I)-C-propeptide synthesize proα2(I) chains that are slow to assemble with proα1(I) chains to form heterotrimers and are retained intracellularly, which might be exposed to altered posttranslational modification. Some alterations, such as c.3952_3953 ins T and c.3487 T > C, lead to the uncharacteristic formation of proα1(I) homotrimers . Compared with the heterotrimer, fiber formation by the homotrimer is impaired, with increased resistance to proteinases . Overall, the mechanisms by which C-propeptide defects cause OI are not well understood. Possible explanations include a reduced type I collagen content in the extracellular matrix, delayed chain initiation and altered posttranslational modification of type I collagen, leading to decreased bone mineralization and bone strength; misfolded type I procollagen heterotrimers can be partly retained in cells, accumulating and increasing endoplasmic reticulum stress . In the present case, the patient’s height was normal; despite generally normal bone imaging, he had multiple brittle fractures. Both heterozygous carriers, the patient’s sister did not exhibit any phenotype of OI, though her daughter experienced one fracture and had mild dentinogenesis imperfecta. Therefore, the COL1A2 (c.4048G > A) mutation appears to be disease causing and result in mild type I OI in this pedigree.
Thus far, four cases of COL1A2 c.G4048A have been reported [10,11,12]. Yasuhiro Hamatani et al. described a 53-year-old male patient with the COL1A2 c.G4048A mutation; diagnoses were OI and mucopolysaccharidosis type (MPS) III, though no gene mutation associated with MPS was discovered. The patient had a short stature, scoliosis, bone fractures, severe mitral regurgitation, and heart failure. Pathological analysis revealed acidic mucopolysaccharide accumulation and relatively few clumps of collagen fibers in the myocardial interstitium, valves, and aorta . Thickening of the interventricular septum was also found in our patient. Nevertheless, considering a 4-year history of hypertension, it is unclear whether this change is related to the type I collagen variant. Huanzheng Li et al. used second-generation sequencing to carry out mutation detection and prenatal diagnosis in an OI family with COL1A2 c.G4048A. The proband had a short stature, blue sclera, and fragility fractures. In contrast, our patient did not have a short stature or blue sclera, different from the above two cases. Another two cases (patient numbers #0001692 and #0002869) are present in Osteogenesis Imperfecta Variant Database (https://www.le.ac.uk/), though the related phenotypes are not reported. One patient (#0001692) was diagnosed with type I OI; however, changes were not found in the affected daughter. Therefore, the COL1A2 c.G4048A mutation results in heterogeneous clinical manifestations in different families and different individuals in a given family.
As early as 1921, Scheuermann described a rigid kyphosis deformity of the thoracic or thoracolumbar spine, known as Scheuermann’s disease . The prevalence of Scheuermann’s disease varies widely in different regions, ranging between 0.4 and 10 % . Although the etiology of Scheuermann’s disease remains unknown, it shows a familial tendency, but the genetic pattern is not clear. Scheuermann’s disease may involve autosomal dominant inheritance. Some environmental factors, such as excess mechanical stress, might also play a role . Lumber Scheuermann’s disease, also known as atypical Scheuermann’s disease or type II Scheuermann’s disease, was first described by Greene et al. in 1987  and is characterized by significant Schmorl’s nodes and endplate irregularity at the thoracolumbar junction without severe clinical kyphosis . A multicenter study reported that the prevalence of the lumbar type in Europe is 8 %, with no significant difference between the sexes . Nevertheless, the prevalence in China has yet to be determined. Schmorl’s node is a herniation of the nucleus pulposus through the endplate into the adjacent vertebral body . The primary function of the vertebral endplate, which is composed of a cartilaginous and an osseous component, is to prevent the intervertebral disc nucleus pulposus from being embedded in the vertebral body and at the same time has the effect of balancing and dispersing stress . Histological studies of Scheuermann’s disease have revealed disorganized endochondral ossification, reduced collagen levels, and increased mucopolysaccharide levels in the vertebral endplate . Some candidate pathogenic genes resulting in Scheuermann’s disease have been reported. For instance, a patient harboring an Arg75-Cys mutation in the collagen type II alpha 1 (COL2A1) gene was found to experience childhood-onset progressive osteoarthritis and vertebral changes, similar to Scheuermann’s disease . Another mutation in the COL2A1 gene (c.1636G > A, p.G546S) was detected in a girl presenting with hip dysplasia and Scheuermann’s osteochondritis . The tryptophan allele of the collagen type IX alpha 3 (COL9A3) gene has also been associated with Scheuermann’s disease and intervertebral disk degeneration . Bertrand Isidor et al. reported a boy with a de novo deletion of the Cullin 4B (CUL4B) gene, mutation of which commonly leads to syndromic X-linked mental retardation (XLMR). In addition to classic presentations of XLMR, such as mental retardation, minor facial anomalies, short stature, hypogonadism, and ataxia, the boy also displayed vertebral anomalies consistent with Scheuermann’s disease and aortic valvular dysplasia, which were new findings . Although an association between Scheuermann’s disease and COL1A1 and COL1A2 was suspected, linkage analysis of three pedigrees failed to identify a relationship .
OI’ s spinal manifestations include scoliosis, kyphosis, craniocervical junction abnormalities, and lumbosacral pathology . To our knowledge, presentations of Scheuermann’s disease have not been previously reported in OI. The COL1A2 c.G4048A gene mutation may hamper the normal formation of type I collagen, affecting the ratio of mucopolysaccharide to collagen and rendering the defective endplates more prone to herniation. Therefore, it is speculated that a fraction of Scheuermann’s disease cases might have underlying dysplasia of bone or cartilage. As a form of skeletal dysplasia, OI might contribute to the occurrence and development of Scheuermann’s disease. Previous studies have indicated that Scheuermann’s disease has a strong association with inheritance, however, related pathogenic genes have not been fully uncovered. With the development of gene sequencing techniques, the pathogenic genes involved in Scheuermann’s disease warrant further study, which helps deepen our understanding of this disease.
We diagnosed this OI patient with Scheuermann’s disease presentation based on multidisciplinary cooperation, including endocrinology, orthopedics, and imaging. Although abnormal fragility fractures may suggest underlying skeletal dysplasia, they might not be given sufficient attention, especially if the fractures are not severe. This case report indicates that it is necessary to pay attention to a history of fragility fractures coexisting with abnormal bone imaging findings. If possible, a detailed examination should be carried out. Strengthening multidisciplinary cooperation may be helpful for the diagnosis and treatment of diseases.
There are some limitations to this article. First, we did not perform lumbar MRI for other family members. Second, experiments using cells to explore the function of the mutant protein were lacking. Therefore, we report this patient as a case report, and further investigation is necessary.
In conclusion, we report an OI patient with the heterozygous c.4048G > A (p.G1350S) mutation in the COL1A2 gene who at the same time exhibited Scheuermann’s disease presentation. This is the first study to reveal the relationship between OI and Scheuermann’s disease. This case enriches the phenotype of OI and offers new insight into the genetic basis of Scheuermann’s disease.